External validation of Cleveland Clinic Foundation colorectal cancer model in a University Clinic in terms of predicting operative mortality.

BACKGROUND: The aim of this study was to perform an external validation of Cleveland Clinic Foundation colorectal cancer model in a single center. METHODS: Relevant data of 771 patients who underwent surgery for colorectal cancer between January 1997 and November 2008 were retrospectively collected. The performance of the scoring system was evaluated by discrimination and calibration. Discrimination was evaluated by using the area under the receiver operator characteristics curve and calibration by using the Hosmer-Lemeshow goodness-of-fit test. RESULTS: Mean age was 60.8 (18-91). Forty-four percent of patients were female, and 56% were male. Overall mortality was 3.9%. Cleveland Clinic Foundation colorectal cancer model showed good discrimination but poor calibration. CONCLUSION: These data suggest that the Cleveland Clinic Foundation colorectal cancer model is a suitable model to be used in our center for patients with colorectal cancer but requires recalibration.

Systemic morphine produce antinociception mediated by spinal 5-HT7, but not 5-HT1A and 5-HT2 receptors in the spinal cord.

BACKGROUND AND PURPOSE: The serotonergic system within the spinal cord have been proposed to play an important role in the analgesic effects of systemic morphine. Currently, seven groups of 5-HT receptors (5-HT1-7) have been characterized. One of the most recently identified subtypes of 5 HT receptor is the 5-HT7 receptor. We aimed to examine the role of spinal 5-HT7 receptors in the antinociceptive effects of systemic morphine. EXPERIMENTAL APPROACH: The involvement of spinal 5-HT7 receptor in systemic morphine antinociception was compared to that of the 5-HT1A and 5-HT2 receptors by using the selective 5-HT7 receptor antagonist, SB-269970, the selective 5-HT1A receptor antagonist, WAY 100635, the selective 5-HT2 antagonist ketanserin as well as the non-selective 5-HT1,2,7 receptor antagonist, metergoline. Nociception was evaluated by the radiant heat tail-flick test. KEY RESULTS: I.t. administration of SB-269970 (10 microg) and metergoline (20 microg) completely blocked the s.c. administered morphine-induced (1, 3, 5 and 10 mg kg(-1)) antinociception in a time-dependent manner. Additionally, i.t. administration of SB-269970 (1, 3, 10 and 20 microg) and metergoline (1, 5, 10 and 20 microg) dose dependently inhibited the antinociceptive effects of a maximal dose of morphine (10 mg kg(-1), s.c.). I.t. administration of WAY 100635 (20 microg) or ketanserine (20 microg) did not alter morphine-induced (1, 3, 5 and 10 mg kg(-1), s.c.) antinociception. CONCLUSION AND IMPLICATIONS: These findings indicate that the involvement of spinal 5-HT7, but not of 5-HT1A or of 5-HT2 receptors in the antinociceptive effects of systemic morphine.

Intralesional treatments for hypertrophic scars: comparison among corticosteroid, 5-fluorouracil and botulinum toxin in rabbit ear hypertrophic scar model.

OBJECTIVE: Different treatment modalities have been used either alone, or in combination to achieve an optimum improvement for hypertrophic scars. Intralesional injections of corticosteroids and 5-fluorouracil are among the most commonly used treatments. Recently, botulinum toxin is proposed as a new treatment option. In this study, it is aimed to compare the efficacies of intralesional triamcinolone acetonide, 5-fluorouracil and botulinum toxin-A for hypertrophic scars. In order to minimize the variables affecting scar formation, standardized wounds in rabbit ear hypertrophic scar model was used. MATERIALS AND METHODS: Four surgical wounds were created on both ears of eight rabbits. Injections to be compared (triamcinolone acetonide, 5-fluorouracil, botulinum toxin-A and control) are administered intralesionally to established scars on day 30. Scars were harvested on day 60 for morphometric analysis including hypertrophic index, fibroblast density, and relative collagen density. RESULTS: Triamcinolone acetonide and 5-fluorouracil injections decreased hypertrophic indexes significantly compared to botulinum toxin-A and control group. However, only 5-fluorouracil was effective to reduce fibroblast counts significantly. No statistically significant differences were found between the treatment groups in terms of collagen index. CONCLUSIONS: According to the results of our study, triamcinolone acetonide and 5-fluorouracil are comparatively effective as monotherapy, but botulinum toxin-A was not effective on established hypertrophic scars.

The effect of FAAH, MAGL, and Dual FAAH/MAGL inhibition on inflammatory and colorectal distension-induced visceral pain models in Rodents.

BACKGROUND: Recent studies showed that the pharmacological inhibition of endocannabinoid degrading enzymes such as fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) elicit promising analgesic effects in a variety of nociceptive models without serious side effects. However, the full spectrum of activities is not observed upon inhibition of either FAAH or MAGL enzymes alone and thus dual FAAH and MAGL inhibitors have been described. Visceral pain is strongly associated with inflammation and distension of the gut. Thus, we explored the comparable effects of FAAH, MAGL, and dual FAAH/MAGL inhibitors on inflammatory and mechanically evoked visceral pain models. METHODS: Visceral inflammatory and distension-induced pain were assessed with the 0.6% acetic acid writhing test in mice and colorectal distension (CRD) test in rats, respectively. The selective FAAH inhibitor PF 3845, MAGL inhibitor JZL 184, dual inhibitor JZL 195, and the cannabis analog CP 55,940 were given systemically 30 min prior to nociceptive testing. KEY RESULTS: PF 3845 (5, 10, and 20 mg/kg), JZL 184 (5, 10, and 20 mg/kg), and JZL 195 (5, 10, and 20 mg/kg) elicit dose-dependent antinociceptive in the acetic acid writhing test. In the CRD model, while JZL 195 (5, 10, or 20 mg/kg) and PF3845 (10, 20, and 40 mg/kg) produced dose-dependent antinociceptive effects comparable to those of CP 55,940 (0.1, 0.3, or 1 mg/kg), JZL 184 (10, 20, and 40 mg/kg) alone did not alter the visceromotor response (VMR). CONCLUSIONS & INFERENCES: The selective FAAH inhibitor and dual FAAH/MAGL inhibitors were effective in both inflammatory and mechanically evoked visceral pain, while the MAGL inhibitor elicited an analgesic effect in inflammatory, but not in distension-induced, visceral pain.

Pronociceptive effects of spinal dynorphin promote cannabinoid-induced pain and antinociceptive tolerance.

Recent studies indicate that sustained opioid administration produces increased expression of spinal dynorphin, which promotes enhanced sensitivity to non-noxious and noxious stimuli. Such increased "pain" may manifest behaviorally as a decrease in spinal antinociceptive potency. Here, the possibility of similar mechanisms in the antinociception of spinal cannabinoids was explored. Response thresholds to non-noxious mechanical and noxious thermal stimuli were assessed. Antinociception was determined using the 52 degrees C tail-flick test. Mice received repeated WIN 55,212-2, its inactive enantiomer, WIN 55,212-3 or vehicle (i.th., bid, 5 days). WIN 55,212-2, but not WIN 55,212-3 or vehicle, produced a time-related increased sensitivity to non-noxious and noxious stimuli. WIN 55,212-2, but not WIN 55,212-3 or vehicle, elicited a significant increase in lumbar spinal dynorphin content at treatment day 5. Increased sensitivity to mechanical and thermal stimuli produced by WIN 55,212-2 was reversed to baseline levels by i.th. MK-801 or dynorphin antiserum; control serum had no effect. WIN 55,212-2, but not WIN 55,212-3 or vehicle, produced dose-related antinociception and repeated administration resulted in antinociceptive tolerance. While MK-801 and dynorphin antiserum did not alter acute antinociception produced by WIN 55,212-2, these substances significantly blocked antinociceptive tolerance when given immediately prior to WIN 55,212-2 challenge on day 5. Daily MK-801 pretreatments, prior to WIN 55,212-2 injection, also produced a significant block of antinociceptive tolerance. These data suggest that like opioids, repeated spinal administration of a cannabinoid CB1 agonist elicits abnormal pain, which results in increased expression of spinal dynorphin. Manipulations that block cannabinoid-induced pain also block the behavioral manifestation of cannabinoid tolerance.

Effects of Ca2+ channel blockers on apomorphine, bromocriptine and morphine-induced locomotor activity in mice.

The effects of L-type voltage-dependent Ca2+ channel blockers on apomorphine, bromocriptine and morphine-induced changes in locomotor activity were examined in mice. Apomorphine (4 mg/kg) and morphine (20 mg/kg) produced locomotor stimulation. Bromocriptine (8 mg/kg) produced a biphasic effect on motor behaviour, an early depressant phase, followed by locomotor stimulation. Amlodipine (2.5 mg/kg), nicardipine (10 mg/kg), diltiazem (10 mg/kg) and verapamil (10 mg/kg), which by itself did not affect locomotor activity, inhibited the stimulant phase of bromocriptine without altering the depressant phase, while they did not affect apomorphine- and morphine-induced locomotor stimulation. Apomorphine, bromocriptine and morphine-induced locomotor stimulation was decreased by SCH 23390 (R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7- ol) (0.05 mg/kg) or haloperidol (0.1 mg/kg). These results indicate that L-type voltage-dependent Ca2+ channels are involved in the motor stimulant effect of bromocriptine, but not in apomorphine- and morphine-induced locomotor stimulation. The effects of Ca2+ channel blockers on the dopaminergic system appears not to be directly related to dopamine receptor blockade.

Peripheral and spinal antihyperalgesic activity of SIB-1757, a metabotropic glutamate receptor (mGLUR(5)) antagonist, in experimental neuropathic pain in rats.

Recent studies suggest a role of Group 1 metabotropic glutamate receptors in mediating the development of spinal hypersensitivity in some pain states. Here, the possible role of mGluR(5) receptors in experimental neuropathic pain elicited by ligation of spinal nerves (L(5)/L(6) spinal nerve ligation, SNL) was explored with SIB-1757, a selective mGluR(5) antagonist. SNL-induced tactile allodynia was detected by decreased paw withdrawal thresholds to probing with von Frey filaments and thermal hyperalgesia by decreased paw withdrawal latencies to radiant heat applied to the plantar aspect of the hindpaw. SIB-1757 was given by either intrathecal (i.th.), subcutaneous (s.c.) or intraplantar (i.pl.) injection. In SNL rats, i.th. SIB-1757 produced a partial reversal of tactile allodynia with a shallow dose-response curve ranging over three-orders of magnitude; SIB-1757 was inactive against allodynia when given systemically. SIB-1757 produced full reversal of thermal hyperalgesia in SNL rats following administration either spinally or locally to the injured paw; administration to the contralateral paw had no effect. SIB-1757 did not produce antinociception in either the SNL or sham-operated rats by any route. These data suggest a significant modulation of thermal hyperalgesia by mGluR(5) antagonists, consistent with reports that this receptor may be associated with afferent C-fibers. The less impressive effect seen on tactile allodynia, likely to be mediated by large fiber input, suggests that the observed modulation may be related to blockade of mGluR(5)-mediated spinal sensitization. These results do not support the involvement of these receptors in modulation of acute nociception but suggest the possibility of a role for Group I mGluRs in the mediation of aspects of neuropathic pain which may be associated with C-fiber inputs.

Effects of neomycin on the development of tolerance to morphine antinociception.

The effects of neomycin on the development of tolerance to morphine antinociception were examined in mice. Because neomycin did not readly cross blood brain barrier, we examined the effects of neomycin following systemic, intracerebroventricular (i.c.v.) and intrathecal (i.t.) injections on the morphine tolerance. Daily subcutaneous (s.c.), i.c.v. and i.t. injections of morphine produced tolerance regardless of route of administration. Both i.c.v. and i.t. neomycin, which alone produced no changes in the basal tail flick latencies, significantly attenuated the development of tolerance to antinociception produced by repeated systemic morphine, while intraperitoneal (i.p.) administration of neomycin did not affect morphine tolerance. Further, i.c.v. and i.t. neomycin attenuated the development of tolerance to antinociception produced by repeated i.c.v. and i.t. morphine, respectively, which were not attenuated by systemic neomycin. This results indicate a potential role for neomycin-sensitive Ca2+ channels on the development of tolerance to the morphine antinoception.

Acute high dose-fentanyl exposure produces hyperalgesia and tactile allodynia after coronary artery bypass surgery.

OBJECTIVE: Opioid-induced hyperalgesia is well known complication of acute high dose and chronic opioid therapy. In this study, we evaluated development of opioid-induced hyperalgesia following intraoperative short-term use of µ-opioid agonist fentanyl after coronary artery bypass surgery. PATIENTS AND METHODS: 100 patients undergoing elective coronary artery bypass graft surgery is divided into two groups. In group I (low dose), anesthesia was induced with propofol 1-2.5 mg/kg and fentanyl 2 mcg/kg, in group II (high dose) fentanyl 40-70 mcg/kg was used. In group I, propofol 5-10 mg/kg/h, fentanyl 1-3 mcg/kg/h, in group II fentanyl 5-10 mcg/kg/h was used for maintenance of anesthesia. The tactile and thermal thresholds were measured before surgery and in 1st, 3rd and 7th postoperative days by using Von Frey filaments and a thermal source, respectively. RESULTS: Tactile thresholds were significantly decreased at the first (6,08±0.21 and 3.76±0.13 g; p<0.001) and third (6.76±0.24 and 4.96±0.16 g; p<0.001) postoperative days compared to baseline preoperative values (7.72±0.26, and 7.60±0.21 g; p=816) in two groups. Postoperative 1st (13.45±0.33 and 10.05±0.24 sec; p<0.001) and 3rd day (14.77±0.28 and 13.17±0.26 sec; p<0.001) assessments showed a statistically significant thermal hyperalgesia compared to the preoperative baseline values (16.67±0.51 and 16.45±0.42 sec; p=0.997) in two groups. This decrease in both tactile and thermal thresholds returned to baseline control values at the 7th day of measurement. CONCLUSIONS: Our results showed that patients undergoing coronary artery bypass surgery receiving fentanyl anesthesia developed postoperative tactile allodynia and thermal hyperalgesia and this was more prominent in high dose group.

Effects of intrathecally administered aminoglycoside antibiotics, calcium-channel blockers, nickel and calcium on acetic acid-induced writhing test in mice.

1. Antinociceptive effects of intrathecally administered aminoglycoside antibiotics, calcium-channel blockers, nickel and calcium ions on the acetic acid-induced writhing test in mice were examined. 2. Neomycin (0.5-20.0 micrograms/mouse) gentamicin (5-40 micrograms/mouse), nicardipine, diltiazem and verapamil (0.5-80.0 micrograms/mouse) and calcium ions (0.02-1.0 mumol/mouse) exerted a dose-dependent antinociceptive activity on the acetic acid-induced writhing test. Nickel ions (2.5, 5.0 and 10.0 mumol/mouse) were found ineffective in this test. 3. These results suggest that N- and L-type, but not T-type, voltage-dependent calcium channels are implicated in the spinal processing of nociceptive information.

Analgesic effects of amlodipine and its interaction with morphine and ketorolac-induced analgesia.

1. The antinociceptive effects of amlodipine, administered subcutaneously (s.c.), intracerebroventricularly (i.c.v.) and intrathecally (i.t.) were examined with the acetic acid writhing and tail-flick tests in mice. Amlodipine was also tested in combination with morphine and ketorolac. Isobolographic analyses were used to define the nature of functional interactions between amlodipine and morphine or ketorolac. 2. The s.c. (0.1, 1.25, 2.5, 5 and 10 mg/kg), i.c.v. (2.5, 5, 10 and 20 micrograms/mice) and i.t. (2.5, 5, 10 and 20 micrograms/mice) administration of amlodipine exhibited a dose-dependent antinociceptive effect in the writhing test but had no effect on the tail-flick latency. Isobolographic analyses revealed an additive interaction between amlodipine and morphine or ketorolac in the writhing test. 3. These results suggest that amlodipine induces antinociception and increases antinociceptive action of morphine and ketorolac, possibly through a decrease in cellular calcium availability.

Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance.

The nonopioid actions of spinal dynorphin may promote aspects of abnormal pain after nerve injury. Mechanistic similarities have been suggested between opioid tolerance and neuropathic pain. Here, the hypothesis that spinal dynorphin might mediate effects of sustained spinal opioids was explored. Possible abnormal pain and spinal antinociceptive tolerance were evaluated after intrathecal administration of [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]enkephalin (DAMGO), an opioid mu agonist. Rats infused with DAMGO, but not saline, demonstrated tactile allodynia and thermal hyperalgesia of the hindpaws (during the DAMGO infusion) and a decrease in antinociceptive potency and efficacy of spinal opioids (tolerance), signs also characteristic of nerve injury. Spinal DAMGO elicited an increase in lumbar dynorphin content and a decrease in the mu receptor immunoreactivity in the spinal dorsal horn, signs also seen in the postnerve-injury state. Intrathecal administration of dynorphin A(1-17) antiserum blocked tactile allodynia and reversed thermal hyperalgesia to above baseline levels (i.e., antinociception). Spinal dynorphin antiserum, but not control serum, also reestablished the antinociceptive potency and efficacy of spinal morphine. Neither dynorphin antiserum nor control serum administration altered baseline non-noxious or noxious thresholds or affected the intrathecal morphine antinociceptive response in saline-infused rats. These data suggest that spinal dynorphin promotes abnormal pain and acts to reduce the antinociceptive efficacy of spinal opioids (i.e., tolerance). The data also identify a possible mechanism for previously unexplained clinical observations and offer a novel approach for the development of strategies that could improve the long-term use of opioids for pain.